This proposal is to test a key hypothesis about the neural organization of motivation, using newly- developed techniques for the identification and control of neurons in freely-moving animals. Maladaptive motivation plays a central role in a range of common and debilitating human disorders, including drug addictions, compulsions, depression and obesity. An accurate description of the roles of particular brain circuits in motivational subprocesses would be a major advance towards the understanding of these disorders. Lesion studies, drug manipulations and neuroimaging have all implicated the nucleus accumbens as a critical node in motivational information processing. However, the fundamental calculations being performed by this structure remain unclear. A major obstacle to the analysis of accumbens function has been the inability to distinguish the activity patterns of distinct cellular components. In particular, separate sets of accumbens neurons express distinct dopamine receptors, and project to distinct targets. These subpopulations are hypothesized to have dissociable functional roles, respectively enabling and suppressing the translation of motivationally salient signals into action. Prior investigations of neural coding in accumbens have been forced to consider these subpopulations together, but this obstacle can now be overcome using a combination of electrophysiological and "optogenetic" techniques in freely moving mice. The light-sensitive cation channel channelrhodopsin-2 will be selectively expressed in subpopulations of accumbens neurons that express either dopamine D1, or D2, receptors. These cells will be monitored using microelectrodes, and distinguished via their response to brief pulses of laser light. We will test the hypothesis that accumbens core neurons that increase firing to reward-predictive cues predominantly express D1 receptors, while those that decrease firing predominantly express D2 receptors. We will also compare the response of D1- and D2- expressing neurons to amphetamine and to the D2 antagonist eticlopride, to further examine the connection between the firing of specific accumbens neurons and psychomotor activation. In the proposed R21 period we expect to complete the first phase of our research program integrating optogenetics tools into behavioral electrophysiology, while testing simple yet critical hypotheses about the organization of limbic circuits. If funded, in subsequent phases we would make full use of these tools to progressively explore fundamental mechanisms of motivational information processing, and how this goes awry in key human disorders. PUBLIC HEALTH RELEVANCE: This project aims for a better understanding of the neural mechanisms underlying motivation. Success in this project may assist the design of novel therapies for common human disorders that are characterized by inappropriate or inadequate motivation, including drug addiction, depression and obesity.